It seems unlikely FDA will limit use of Biogen Idec and Elan's multiple sclerosis drug Tysabri (natalizumab) to patients who test negative for JC-virus, a possible risk factor for the viral brain infection progressive multifocal leukoencephalopathy.

While Biogen Idec declined to comment directly on this question, in an interview on Oct. 20 discussing how FDA's review of a related labeling change has been pushed back to January, the company said, "FDA has indicated the additional time is just to review changes to the REMS program."

The proposed labeling change would note that a patient's anti-JC virus antibody status is a risk factor for PML - a change that has already been approved for the European label.

Biogen Idec and Elan submitted this proposed change under an sBLA which they filed last Dec. 22 with a standard 10-month review expected. With the extension by FDA, the revised PDUFA date should be about Jan. 22, 2012, although Biogen declined to specify the exact date (Also see "Biogen/Elan Submit Applications For Tysabri Label Change Ahead of Schedule" - Pink Sheet, 23 December, 2010.).

PML Cases Rise With Prescriptions

The labeling update with be the second in a year for the MS drug.

On April 22, FDA announced two labeling changes: the inclusion of a table summarizing rates of PML with Tysabri use according to the number of infusions, and the addition of new information noting patients treated with immune suppressing medications before taking Tysabri have been shown to be at an increased risk for PML. (Also see "U.S. Tysabri Labeling Updated With More PML Risk Info But No Reference To JCV Testing" - Pink Sheet, 22 April, 2011.).

The labeling also warns of a risk when immunosuppressants are taken concomitantly with Tysabri. The JC-virus is thought to cause PML, and testing for its antibodies could increase physicians' and patients' confidence on the drug's risk-benefits balance.

As of April, 111 patients out of 78,800 who had taken Tysabri worldwide had developed PML. As of Oct. 4, that figure had risen to 170 cases out of 88,100 patients, with 33 deaths. The number of U.S. cases of Tysabri patients who had developed PML stood at 64, compared with 98 in the European Economic Area and eight elsewhere in the world.

In April, the companies had data on 27 PML cases from whom there were pre-diagnosis serum samples, all 27 of which had tested positive for JCV. By Oct. 4, that figure has risen to 41 cases that all tested positive.

Clinical Data On Risk Stratification

Biogen Idec and Elan presented data from two studies to support their PML risk stratification initiatives at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis in Amsterdam, which runs from Oct. 19-22.

In a poster presentation, an analysis evaluated PML risk in MS patients based on three risk factors: Tysabri treatment duration, prior immunosuppressant use and anti-JCV antibody serostatus. "Patients who were anti-JCV antibody negative were at lowest risk. Patients who had all three risk factors were at greatest risk," the companies said.

In other poster presentations at the conference, Biogen Idec and Elan presented data showing that MS patients who receive Tysabri early in the course of their disease "experienced significantly reduced annualized relapse rates (ARR) and that Tysabri provided long-term benefit to patients who had achieved short-term freedom from disease activity."

An analysis compared patients in the long-term Safety of TYSABRI Re-dosing and Treatment (STRATA) study who were disease activity free to patients who were not disease activity free over two years in the AFFIRM trial.

At STRATA baseline, there were 177 disease activity free patients and 415 who were not. After three years of Tysabri treatment in STRATA, the patients who were originally disease activity free had less disability and significantly lower ARR than those who had had disease activity. Mean Expanded Disability Status Scale (EDSS) scores were 2.34 for the DAF patients and 3.23 for the patients who had disease activity (p<0.0001), and="" the="" unadjusted="" arrs="" was="" 0.08="" in="" daf="" patients="" and="" 0.16="" in="" ndaf="" patients=""><>

A separate study showed Tysabri-treated patients experienced "improved incontinence-related quality of life," the companies added.

- Martin Berman-Gorvine (m.berman-gorvine@elsevier.com)

Tysabri Usage Restrictions Likely To Remain Stable As FDA Considers REMS Modifications

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